Numerous polymer-based medical devices have been developed for the delivery of therapeutic agents to the body. In accordance with some typical delivery strategies, a therapeutic agent is provided within a polymeric carrier layer and/or beneath a polymeric barrier layer that is associated with a medical device. Once the medical device is placed at the desired location within a patient, the therapeutic agent is released from the medical device at a rate that is dependent upon the nature of the polymeric carrier and/or barrier layer.
Materials which are suitable for use in making implantable or insertable medical devices typically exhibit one or more of the qualities of exceptional biocompatibility, extrudability, elasticity, moldability, good fiber forming properties, tensile strength, durability, and the like. Moreover, the physical and chemical characteristics of the device materials can play an important role in determining the final release rate of the therapeutic agent.
As a specific example, block copolymers of polyisobutylene and polystyrene, for example, polystyrene-polyisobutylene-polystyrene triblock copolymers (SIBS copolymers), which are described in U.S. Pat. No. 6,545,097 to Pinchuk et al., which is hereby incorporated by reference in its entirety, have proven valuable as release polymers in implantable or insertable drug-releasing medical devices. As described in Pinchuk et al., the release profile characteristics of therapeutic agents such as paclitaxel from SIBS copolymer systems demonstrate that these copolymers are effective drug delivery systems for providing therapeutic agents to sites in vivo.
These copolymers are particularly useful for medical device applications because of their excellent strength, biostability and biocompatibility, particularly within the vasculature. For example, SIBS copolymers exhibit high tensile strength, which frequently ranges from 2,000 to 4,000 psi or more, and resist cracking and other forms of degradation under typical in vivo conditions. Biocompatibility, including vascular compatibility, of these materials has been demonstrated by their tendency to provoke minimal adverse tissue reactions (e.g., as measured by reduced macrophage activity). In addition, these polymers are generally hemocompatible as demonstrated by their ability to minimize thrombotic occlusion of small vessels when applied as a coating on coronary stents.
In addition, these polymers possess many interesting physical and chemical properties sought after in medical devices, due to the combination of the polyisobutylene and polystyrene blocks. Polyisobutylene has a low glass transition temperature (Tg) and is soft and elastomeric at room (and body) temperature. Polystyrene, on the other hand, has a much higher Tg and is thus hard at these temperatures. Polystyrene is also thermoplastic in nature, opening up a wide range of processing capabilities. Depending upon the relative amounts of polystyrene and polyisobutylene, the resulting copolymer can be formulated to have a range of hardness, for example, from as soft as about Shore 10A to as hard as about Shore 100D.
Whether the system comprises a SIBS copolymer or other biocompatible polymers, these materials, once incorporated into a finished medical device, typically undergo a sterilization process. Two prevalent sterilization processes are exposure to ethylene oxide (EtO) and irradiation by, for example, gamma or electron beam radiation. For several decades, sterilization using ethylene oxide has been the method of choice for sterilizing medical devices such as catheters, mechanical heart valves, sutures, adhesive bandages, tracheostomy tubes, and so on. The primary advantages associated with the use of EtO sterilization are the low processing temperature and the wide range of compatible materials. However, the toxicity of the gas, its potential carcinogenicity, and concerns over residuals in the product and the manufacturing environment have subjected EtO use to ever increasing regulatory scrutiny and control and continues to escalate the cost of EtO sterilization. In addition, EtO is highly reactive and may interact with or otherwise adversely affect various therapeutic agents present in a medical device.
Radiation sterilization, whether by gamma rays, X-rays, accelerated electrons, or other means, is a widely-used alternative method for sterilizing medical devices. Products to be sterilized are typically exposed to gamma rays from a Co-60 or a Cs-137 source or to machine accelerated electrons until the desired dose is received. No toxic agents are involved, and products may be released for sale on the basis of documentation that the desired dose is delivered. For the sterilization of polymeric medical devices, a typical radiation dose of about 1.0-5.0 Mrad (10-50 kGy) or higher, is employed.
Radiation sterilization, however, may modify many important physical and chemical properties of polymeric materials such as the molecular weight, chain length, entanglement, polydispersity, branching, pendant functionality, and chain termination. These changes in the properties may impact, for instance, the drug-eluting properties of the polymers and impair the performance of a polymer for a specific use. For example, from a product use standpoint, mechanical properties are important characteristics that may be adversely affected by irradiation of polymers. These properties include tensile strength, elastic modulus, impact strength, shear strength, and elongation.
For example, when polymers are exposed to radiation, two basic reactions may occur: (1) chain scission (i.e., a random rupturing of bonds) of polymer molecules and (2) cross-linking of polymer molecules. Crosslinking generally results in the formation of larger, three-dimensional polymer structures. Chain scission, on the other hand, generally results in a decrease in the molecular weight of the polymer molecules. Although both of these reactions commonly occur as polymeric materials are subjected to ionizing radiation, one reaction frequently predominates within a specific polymer. As a result of chain scission, very-low-molecular-weight fragments, gas evolution, and unsaturated bonds may appear. Cross-linking generally results in an initial increase in tensile strength, while impact strength decreases and the polymer becomes more brittle with increased dose.
For polymers with carbon-carbon backbones, it has been observed that cross-linking generally will occur if the carbons have one or more hydrogen atoms attached, whereas chain-scission generally occurs at tetra-substituted carbons. Polymers containing aromatic molecules are generally more resistant to radiation degradation than are aliphatic polymers; this is true whether or not the aromatic group is directly in the chain backbone or not. Thus, both polystyrenes, with a pendant aromatic group, and polyimides, with an aromatic group directly in the polymer backbone, are relatively resistant to high doses (>4000 kGy). On the other hand, homopolymers and copolymers containing polyisobutylene such as a SIBS copolymer are generally more susceptible to radiation effects and may undergo chain scission during irradiation, especially at the radiation levels typically used for medical device sterilization (e.g., about 2.5 Mrad). A summary of the effects of radiation on polymer properties, such as loss of elongation, for a number of common thermoplastics and thermosets is provided in “Polymer Materials Selection for Radiation-Sterilized Products” by Karl J. Hemmerich, Medical Device & Diagnostic Industry Magazine, February 2000, pp. 78-89, the entire contents of which are hereby incorporated by reference.
Radiation issues are particularly pronounced in medical devices having thin polymer coatings. This is especially true where a radiation sensitive polymer such as a SIBS copolymer is provided in the form of a thin coating on the surface of an expandable medical device such as a stent or balloon. For example, radiation can lead to an unacceptable increase in the surface tack of the SIBS copolymer, which can in turn cause defects in the polymer when it is expanded (e.g., in situations where it is in the form of a coating on the surface of an expandable stent or balloon).
Additionally, SIBS copolymers present special synthesis challenges. Currently, SIBS copolymers are synthesized by a living cationic polymerization process, a complex process that requires stringent reaction conditions and low temperatures. Ionic (cationic and anionic) polymerizations typically require reaction conditions free of moisture, oxygen, as well as impurities. To date, only a limited number of monomers have been polymerized by a living cationic polymerization process, thus restricting the ability to vary the chemical composition of polymers and copolymers produced by this process. Further, the experimental rigor generally involved in ionic polymerizations is often too costly for industrial use and free radical routes are preferred.
Hence, it would be advantageous to provide polymers that have various properties that are analogous to those of SIBS copolymers (e.g., drug release characteristics and biostability/biocompatibility) but which also exhibit improved immunity to radiation-based changes in polymer properties and are easier to synthesize using a wider array of monomer materials.